Vesamicol is a well known lipophilic analogue of the choline precursor deanol. In small to moderate doses, vesamicol induces respiratory paralysis and death in laboratory animals. Investigations of the mechanism underlying the actions of vesamicol led to the identification of a vesicular acetylcholine transporter (VAChT). VAChT is a protein complex which transports acetylcholine (ACh) from its site of synthesis in the cytosol into the synaptic vesicle. The latter serves as the primary vehicle for stimulus-induced release of acetylcholine (and other neurotransmitters) into the synapse. Vesamicol and related compounds have been shown to bind to a specific locus (the vesamicol receptor or VR) on the VAChT and thus to non-competitively inhibit the transport of ACh into the synaptic vesicle. Since the latter serves as the primary release vehicle for ACh, inhibition of synaptic vesicle loading eventually results in a cholinergic deficit at the synapse.
Consistent with this mechanism, vesamicol has no effect on pre-loaded vesicles, and vesamicol-mediated anti-cholinergic effects are frequency-dependent (reflecting the depletion of a pre-loaded vesicle pool). The identification of the VAChT provides another point for potential regulation of cholinergic function. Previously known targets include acetylcholinesterase (AChE), the sodium-dependent high affinity choline transporter (SDHAChT), choline acetyl transferase (ChAT) and muscarinic and nicotinic receptors. Moreover, the availability of vesamicol, a prototypical antagonist for the VAChT, provides an alternative method for modulating cholinergic function in the central and peripheral nervous system.
Although vesamicol is a potent inhibitor of VAChT, the compound also displays .alpha.-adrenoceptor activity. Moreover, vesamicol exhibits nanomolar affinity for sigma receptors. This lack of selectivity limits the use of vesamicol as a VAChT inhibitor. Compounds related to vesamicol are disclosed in U.S. Pat. Nos. 5,338,852, 5,358,712, and 5,457,207. Although VAChT inhibitors which are more potent and selective than vesamicol have been reported, these compounds are typically more lipophilic than vesamicol and therefore attain only limited access to the brain. Currently, there is a need for novel, potent, and selective VAChT antagonists and agonists of moderate lipophilicity, which display enhanced penetration into the central nervous system.